Central thalamic deep brain stimulation (CT-DBS) is a promising therapy for restoring consciousness in patients in coma and vegetative state by changing the arousal state. Early experimental studies have established a causal link between central thalamus electrical brain stimulation and forebrain arousal. Clinical investigators in the 1960s and 1970s considered the potential relevance of the findings as a method for restoration of arousal and consciousness in chronically unconscious patients and carried out pilot case studies of electrical stimulation. However, despite eye opening and autonomic signs consistent with arousal effects, no reports described sustained recovery of interactive behavior. Following on these early case reports, a multicenter study involving a total of 49 patients was carried out. Deep brain stimulation resulted in increases in arousal and associated physiological responses in the majority of these patients but there were unfortunately no changes in behavioral responsiveness. More recently, a single subject study provided the first compelling evidence that some severely brain injured patients in minimally conscious state (MCS) may benefit from CT/DBS. The overall findings indicated significantly improved behavioral responsiveness with a combination of immediate as well as slowly accumulating, though long-lasting effects. However, this type of response has only been observed in a single subject and has been difficult to reproduce. While these earlier findings raise the possibility that using CT/DBS to improve consciousness in severe traumatic brain injury could be efficacious, many critical challenges lay ahead. These include defining the mechanisms of action and optimizing stimulation targets and parameters to make CT/DBS a reliable clinical treatment. In this proposal, we aim to overcome these challenges. We will develop and utilize a novel optogenetic functional magnetic resonance imaging approach that will enable us to systematically understand the underlying mechanism of action of the CT/DBS therapy with unparalleled clarity. Elucidating the mechanism of CT-DBS therapy will allow us to optimize the stimulation target, stimulation parameters, and even help stratify patients for inclusion into such therapeutic modalities. In Preliminary Studies we have established the effectiveness of the ofMRI approach at identifying key locations of stimulation and, importantly, function associated with CT-DBS. We will first conduct ofMRI, EEG, and behavioral studies in normal animals to define circuit mechanisms involved in both acute and long-term stimulation. Then, we will evaluate the optimized parameters of stimulation and their role in restoring consciousness in animal models of TBI. Knowledge of CT-DBS mechanism and optimization parameters will be invaluable for future clinical trials, understanding of mechanisms of arousal, consciousness, and neuromodulation therapy.